Growing evidence reveals that alterations in autophagy occur in many human diseases. Here we discuss only those disorders in which autophagy malfunction has been shown to contribute to their pathogenesis (). As mentioned above, autophagy occurs at basal, constitutive levels and recent studies have highlighted the importance of basal autophagy in intracellular quality control. The demand for basal autophagy differs among tissues; it is particularly important in the liver and in other tissues where the cells, such as neurons and myocytes, do not divide after differentiation18,19,23–25
. In contrast to conventional atg5
atg5 and beclin 1
knockout mice, which die during embryogenesis or the neonatal period1,23,26–29
, those with neural-tissue-specific knockouts of these genes survive the postnatal starvation period. However, these mice develop progressive motor deficits and display abnormal reflexes, and ubiquitin-positive inclusion bodies accumulate in their neurons18,19
. Although the levels of autophagosomes detected in neurons are very low under normal and even starvation conditions30,31
, these studies strikingly show that constitutive turnover of cytosolic contents by autophagy is indispensable, even in the absence of expression of any disease-associated mutant proteins.
The role of autophagy in human disease
Despite the important function of basal autophagy in healthy individuals, the requirement for autophagy is even more evident under disease conditions. Recent studies reveal that degradation of disease-related mutant proteins is highly dependent on autophagy, in addition to the ubiquitin–proteasome system. Examples include extended polyglutamine-containing proteins that cause various neurodegenerative diseases such as Huntington’s disease and spinocerebellar ataxia, and mutant forms of α-synuclein that cause familial Parkinson’s disease32–34
. CMA also participates in wild-type α-synuclein degradation, but mutant forms of α-synuclein block the lysosomal receptor, resulting in general CMA inhibition35
. The affected cells attempt to compensate for the CMA blockage by upregulating macroautophagy, which guarantees cell survival but renders the cells more susceptible to stressors4
Considering all of the available data, there is no doubt that autophagy has a beneficial effect of protecting against neurodegeneration; however, how autophagy can prevent neurodegeneration is not completely understood. One hypothesis is that autophagy eliminates protein aggregates or inclusion bodies, possibly in a directed manner36,37
. One possible adaptor is p62/sequestosome-1 (SQSTM1)36
. Almost all protein aggregates are decorated with ubiquitin, and SQSTM1 has both LC3-binding (the mammalian homologue of the autophagy-related protein Atg8) and ubiquitin-binding domains, allowing it to mediate the recognition of protein aggregates by a protein (LC3) in the membrane of the forming autophagosome36,38
. Furthermore, proper turnover of p62 by autophagy is critical to prevent spontaneous aggregate formation39
However, direct degradation of aggregates by autophagy is somehow contradictory to the recent hypothesis that the generation of protein aggregates is a protective mechanism40,41
. Rather, the primary target of autophagy seems to be diffuse cytosolic proteins, not inclusion bodies themselves, suggesting that inclusion body formation in autophagy-deficient cells is an event secondary to impaired general protein turnover18
. However, it is still possible that misfolded proteins in soluble or oligomeric states could be preferentially recognized by autophagosomal membranes, which might also be mediated by ubiquitin–p62–LC3 interactions.
Alterations of autophagy have also been observed in Alzheimer’s disease, but in this case the contribution of autophagy may not be as simple as in other types of neurodegeneration. For example, autophagosome-like structures accumulate in dystrophic neurites of Alzheimer’s disease patients and model mice, probably owing to impairment of autophagosome maturation into autolysosomes ()42
. Surprisingly, the toxic proteolytic product Aβ can be produced within these partially degraded compartments because the Aβ precursor protein, APP, and the protease responsible for its cleavage, are both present in the endoplasmic reticulum sequestered in these structures42
. Therefore, one hypothesis is that impaired autophagic flux provides a novel site for Aβ peptide production.
It is reasonable to assume that autophagy could be a therapeutic target for treatment of these neurodegenerative diseases because of its protective role43
. For example, upregulation of autophagy by the regulatory protein kinase complex Target of Rapamycin (TOR) inhibitors such as rapamycin and its analogue CCI-779 protects against neuro-degeneration seen in polyglutamine disease models in Drosophila
. Recently, small-molecule enhancers of rapamycin were identified45
. These improve the clearance of mutant huntingtin and α-synuclein, and protect against neurodegeneration in a fruit-fly Huntington’s disease model. Importantly, the effects of small-molecule enhancers of rapamycin are independent of TOR, making it possible to use them in combination with rapamycin for therapeutic purposes. In any attempt at manipulating autophagy therapeutically, however, it is important to take into account the dynamic nature of the changes that occur in the autophagic system during the pathogenic course of a disease ().